The present invention relates generally to a cooling catheter medical device such as may be used to guide interventional tools and to reduce reperfusion tissue injury, injury resulting after periods of ischemia, occurring naturally, through trauma, or from surgery, and further relates to the application of adjunctive therapies such as angioplasty and stent placement.
Heart disease is the leading cause of death in the United States. For heart attack, the primary treatment goal is rapid blood flow restoration to ischemic tissue. Despite the success of thrombolytic drugs and percutaneous coronary intervention (PCI) to reperfuse ischemic tissue, about 20% of all patients die within the first year following their first heart attack. Reperfusion is paradoxical, as reperfusion both saves tissue and kills tissue. Reperfusion injury is a critical barrier to improved patient outcomes, accounting for up to 50% of tissue injury. Reperfusion injury results in myocyte damage through myocardial stunning, microvascular and endothelial injury, and irreversible cell damage or necrosis.
A 2004 National Heart, Lung, and Blood Institute expert working group stated that current reperfusion therapies that included angioplasty, thrombolytics, and coronary bypass surgery have plateaued; new adjunctive therapies are needed to further improve patient outcomes. Quantitatively speaking: these strategies need to reduce infarct by 35% to reduce mortality rates in humans. In addition, the treatment method must not significantly alter current standards of care nor delay reperfusion.
Experimental evidence has shown that reductions in tissue temperature can reduce the effects of ischemia or inadequate blood flow and subsequent reperfusion. Hypothermia decreases tissue metabolism, microvascular obstruction and no reflow, oxygen free radical production, intercellular calcium overload. Hypothermia also inhibits platelet aggregation and preserves ATP and glycogen stores
Despite hypothermia therapy's potential to attenuate myocardial necrosis, no cooling device has achieved approval for percutaneous coronary intervention because: 1) they complicate or impede the care path; and 2) they have not demonstrated significant clinical benefits. Reducing lingering heart damage following a heart attack due to reperfusion injury continues to be a large unmet need.
There are two broad categories of devices used to harness the therapeutic value of hypothermia: external systems and internal systems. Within these categories, subcategories of whole-body and regional cooling exist. Originally whole-body external systems consisted of immersion in cold water or forced cold air through blankets. An advanced external cooling system by U.S. Pat. No. 6,375,674 B1 to Carson, significantly improved cooling rates by adding a conductive adhesive layer between the skin and device, coolant pathways that provide relatively high speed coolant flows with resulting higher level convective heat transfer coefficients, and an insulated outer layer to the external walls to ensure heat addition from the ambient is minimal. While this approach is considered noninvasive, rapid temperature drop of organs at risk is not possible, rates of body temperature decrease are only about 3.2 degree Celsius per hour.
Invasive or vascular whole-body coolers have also been created, as shown in exemplary U.S. Pat. No. 6,096,068 to Dobak et al., U.S. Pat. No. 6,126,684 to Gobin et al., and U.S. Pat. No. 6,231,594 to Dae. In each of these cases, catheters are placed in a large vein called the vena cava. Passive heat transfer enhancement techniques are used to accelerate whole body cooling. These techniques consist of either increasing surface area, increasing fluid mixing or turbulence, or increasing both surface area and turbulence simultaneously. Again, these approaches do not allow for rapid organ cooling; whole-body cooling rates range from 2 to 5 degrees Celsius per hour. These passively enhanced techniques also consume fluid kinetic energy, reducing blood flow and potentially re-creating ischemic conditions, making them less suited for low flow, small diameter applications as found in organ arteries. The vena cava has an inner diameter of approximately 22 mm carrying 5000 ml/min of blood flow; in comparison a left coronary artery has an inner diameter of approximately 4 mm carrying 125 ml/min of blood flow. Alternative patents, such as U.S. Pat. No. 7,211,066 to Merrill describe active enhancement methods that avoid kinetic energy dissipation and are more suited for organ arteries such as the left coronary artery and a carotid artery.
Current research indicates that more rapid cooling is needed to reduce the final extent of organ damage following ischemic events such as stroke and heart attack and improve patient outcomes. A cooling rate of 4 degrees Celsius in five minutes (48 degrees Celsius per hour) has been suggested. This represents an order of magnitude increase in cooling capacity compared to whole-body cooling devices. In addition whole-body cooling has additional limitations and drawbacks related to its inherent unselective nature. Research has shown that systemic or whole body cooling may lead to cardiovascular irregularities such as reduced cardiac output and ventricular fibrillation, an increased risk of infection, and blood chemistry alterations.
Few concepts have attempted local, organ-specific cooling. Local cooling approaches have been limited by the technological challenges related to developing sufficiently small heat exchangers for small arterial vessels. These vessel inner diameters are typically less than 6 mm, whereas larger systemic vessels are 20 mm or larger. The key advantage to localized or organ level cooling is the reduced thermal inertia, since the cooling capacity required is directly proportional to the product of the mass and specific heat. Cooling 100 grams of heart tissue (approximately one-third of the heart) vs. an entire 70,000 gram patient takes significantly less cooling capacity to reach equivalent reduced temperatures. In addition the rate of cooling is substantially greater with localized organ specific cooling.
One ideal application for organ-specific cooling is emergency angioplasty. When patients suffer a heart attack there are three broad categories of care: thrombolytics—breaking done a blood vessel blockage with chemicals, coronary artery bypass surgery—creating a bypass around a vessel blockage, and emergency angioplasty. The emergency angioplasty care path has been well-established since the 1980's. In this case the reperfusion event, when the blood rate resumes to levels above critical ischemic thresholds, is controlled by the physician and medical staff. Therapeutic hypothermia applied during emergency angioplasty is considered an adjunctive therapy.
Angioplasty involves recanalization or reopening of block organ arteries with dilation or balloon catheters. Prior to recanalization there is a stenosis or blockage preventing adequate blood to the organ of interest, creating an ischemic event that eventually leads to a reperfusion event if the stenosis can be removed. As each minute passes with flow completely halted or below an ischemic threshold of 0.12 to 0.24 ml/min/g of tissue, more organ tissue is lost. Organ tissue closest to the blockage, called the ischemic core, is most vulnerable to irreversible damage. The region between healthy perfused tissue and the ischemic core is called the pneumbra. This is the region that has the potential of being saved with effective adjunctive therapies.
To understand how therapeutic hypothermia may be an effective adjunctive therapy an overview of the angioplasty care path is needed. Critical medical devices used during this procedure will be discussed immediately in the following paragraphs. Coronary angioplasty with a single stenosis begins with the insertion of an introducer or insertion sheath used to enable access to the patient's vascular system. Once the patient activating clotting time (ACT) has been altered by heparin or similar agent to avoid thrombus formation on the interventional tools, a guide catheter is threaded into the insertion sheath towards the coronary artery of interest. Once at the ostium or intersection of the aorta and the coronary artery, the distal tip (the end of the catheter) engages the coronary artery and a baseline angiogram is conducted. A baseline angiogram uses contrast agent (a fluid that can be seen through fluoroscopy) to establish the precise location of the stenosis. After the location of the stenosis has been identified, a guide wire is steered across the stenosis. With the guide wire fixed in place a dilation or balloon catheter is threaded along the guide wire and towards the stenosis. Once the dilation catheter balloon is positioned directly inside the stenosis, the balloon is inflated progressively, compressing the lesion or blockage material radially outward. In addition to balloon dilation today's interventional tools also include stents that are metal supports to avoid restenosis and thrombectomy devices that mechanically remove lesion material. Once acceptable perfusion and or reperfusion are established and verified through angiograms, the dilation catheter, the guide wire, and the guide catheter are removed. Finally the insertion sheath is removed and the patient is moved to a recovery area where the penetration wound heals and the patient is monitored.
An effective therapeutic hypothermia device that is organ-specific needs to integrate with the emergency angioplasty care path, taking into account the physical features and operational aspects of the medical devices or components used.
The insertion sheath provides an entry pathway into the vascular system, connecting the outside world to the vascular world. It is a tapered tube with a hemostat, a one-way valve to prevent blood loss. A side port allows secondary blood access to monitor blood characteristics during procedures and the tapering minimizes the wound size resulting from angioplasty.
Guide catheters are threaded through the insertion sheath and their simple exterior hides their complexity. Guide catheters serve four functions: 1) they are a conduit for device and wire transport, 2) they support device advancement (in some cases lesions are not easily traversed by dilation catheters), 3) they are conduits for contrast injection, and 4) they provide a means for blood pressure measurement. To perform these functions they must have these physical features: 1) a rear hub that allows for easy and secure connections with interventional devices such as guide wires, thrombectomy devices, dilation catheters, and manifolds for pressure measurement and contrast delivery; 2) a distal tip shape that integrates well with patient anatomy so that the catheter and artery are coaxial; 3) a distal tip material that is radiopaque so that it can be visualized with fluoroscopy; 4) a distal tip that will not damage vessels, also called atraumatic; 5) a shaft that allows for torque control to guide the distal tip correctly; 6) a shaft that is kink resistant; 7) a shaft with an inner diameter sufficiently large or compatible to pass interventional tools (dilation, stent, thrombectomy, etc.); 8) a shaft that is sufficient rigid or stiff to provide support for interventional device placement and will not dampen pressure signals; and 9) a shaft that is lubricious, meaning a shaft material that allows interventional tools to pass easily.
Medtronic, a leading manufacturing of guide catheters such as the Launcher™ guide catheter, lists 28 distal shapes or curves for catheter shafts available to physicians. Proper placement of the guide catheter will largely depend on these distal shapes and active rotation of the catheter by the physician. The contralateral wall, the wall opposing the ostium, is typically used to support or buttress final placement. Proper engagement of the ostium requires coaxial alignment and some annular space between the catheter outer wall and the inner wall of the ostium, avoiding arterial flow occlusion. To meet the shaft functionality the walls of a guide catheter are usually a composite of polymers and metal, as shown in U.S. Pat. No. 5,531,721 to Pepin et al. The outer wall is designed to be smooth and hemocompatible, a stainless steel braid provides the mechanical properties, and finally an inner low coefficient of friction polymer is used as a inner liner or coating.
Guide wires range in size from 0.010 to 0.038 inches. To ensure ease of placement across lesions a variety of stiffness levels are used at the distal tip. Shaping of the distal tip is also possible. Surface coatings, such as hydrophilic coatings enhance maneuverability. Guide wire torque devices, located outside the guide catheter hub, are attached to the proximal end and radiopaque materials at the distal end help ensure precise placement under fluoroscopy.
Dilation catheters provide the radial force to reduce the amount of cross sectional area blockage occurring at a lesion. Thanks to improved balloon design, balloon materials (such as polyethylene (PE) and polyethylene terphalate (PET)), and balloon wrapping techniques improved patient outcomes have been achieved. Typical catheters like the Medtronic Sprinter® OTW have crossing profiles that are 0.021-0.024 inches (0.53 mm to 0.61 mm), where the crossing profiles is the diameter of the balloon in a fully wrapped and collapsed position. Lesion entry profiles, the diameter at the distil tip of the dilation catheter, are 0.016 inches (0.41 mm). Catheterization guidelines recommend that the crossing profile be at most one-half the inner lumen of the guide catheter to ensure low force passage to the artery of interest. At these pre-inflation profiles, fully inflate balloon diameters range from 1.5 to 4.0 mm at pressures ranging from 4 to 18 atmospheres. In addition to these geometric characteristics today's dilation catheters also use shafts that are designed for trackability, the ability to follow along tortuous paths, and pushability, the ability to force through a lesion provided it has sufficient stiffness. Finally, surface coatings are used to improve surface lubricity so that frictional resistance is minimized.
While rapid localized organ cooling may potentially reduce damage from ischemia few references have described a way to integrate into the emergency angioplasty care path. Often, the physical features of conventional catheter medical devices do not allow for integration with emergency angioplasty interventional tools, namely from a flexibility and size perspective. In addition because they rely on passive heat transfer enhancement methods blood flow resistance to increases, reducing perfusion to already damaged organs recovering from ischemic events. This blood resistance comes as a direct of result of the design features: 1) an enhanced surface area (more area for flow-resistive shear stress to act upon) 2) a cooling surface geometry that causes increased fluid mixing (causing viscous dissipation of kinetic energy), and 3) a reliance on the pumping power of the heart to push fluid over the heat exchanger surfaces (energy from the heart provides the energy require for mixing).
U.S. Pat. No. 6,645,234 to Evans et al. describes a cardiovascular guiding catheter with heat exchange properties. In this patent there are five lumens and inflatable external balloons used to exchange heat away from systemic blood flow in the descending aorta, the major artery leaving the heat. This design provides a means for systemic or whole-body cooling while also acting as a guide catheter. Whole-body cooling, however, does not address organ-specific reperfusion injury resulting after an ischemic event, the clinical problem that this patent addresses As described earlier, there are several existing external and internal whole-body cooling devices that produce cooling rates ranging from 2-5 degrees Celsius per hour. In addition to not providing a means for rapid organ-specific cooling, the '234 Evans et al. device has several disadvantages from a guide catheter perspective. First, braiding does not extend to the distal tip in this patent, removing a critical physical feature necessary to provide support of dilation catheter placement and kink resistances. Second, inflation and deflation of the external balloons make device removal from the patient more difficult and will likely require a large insertion sheath than is typically needed. Increased insertion sheath sizes lead to longer healing times and increased complications, the motivation in the commercial market for continued reduction in guide catheter sizes since the angioplasty procedure was introduced. Third, the external balloons will naturally limit the maneuverability of the distal tip as the walls of the aorta are used to buttress or support proper guide catheter placement. Fourth, the lubriciousness of the inner and outer surfaces is unclear. Typically Teflon is used to reduce the friction resistance in guide catheters. External balloons add significantly more area over which friction forces act. Finally, these external balloons create significant blood stagnation zones as the catheter contacts the aorta in comparison to standard guide catheters. Based on cardiovascular support design fundamentals, these zones are considered likely locations for thrombus or clot generation.
U.S. Pat. No. 6,033,383 to Ginsburg, U.S. Pat. No. 5,180,364 to Ginsburg, and U.S. Patent Application Publication No. 2001/0005791 A1 to Ginsburg each describe temperature regulating devices for controlling liquid medium temperatures inside a patient. The Ginsburg devices have several disadvantages against application to reduce tissue damage arising from reperfusion injury following emergency angioplasty procedures. To ensure adequate cooled blood is delivered safely and easily during an emergency angioplasty procedure, described above, many of physical features and functions of existing angioplasty equipment are needed. The design intent of the '383 Ginsburg device is clearly to transfer fluids, not interventional tools associated emergency angioplasty. As a result, embodiments do not address torque control, kink resistance, and support characteristics through catheter shaft design. Regarding the inner most lumen, lubriciousness or friction-resistance is not addressed. Internal flaps represent an order of magnitude increase in surface roughness relative to the roughness of typical coatings and liners used to deliver interventional tools. Teflon, the standard coating, has a roughness around 6e−5 inches or 1.52e−3 millimeters.
The flaps shown in the Ginsburg devices could not operate as described. First to properly seal the inner, a rectangular leaflet or flap would need to bend or curve along the curvature of the inner diameter of the inner lumen. Second, even if the flap was bent to meet the radius of curvature of the inner diameter of the circular device, flap deflection would be inhibited or perhaps prohibited completely because of the orthogonal curvature relative to the desired axis of rotation. No existing catheters implement this valve design. Embodiments do not describe the distal tip requirements necessary for effective, safe, and easy placement for rapid organ-specific cooling as in emergency angioplasty. For example to engage the ostium of the heart these embodiments do not describe the necessary shape or shaft support necessary to locate and deliver interventional tools. In fact, if the double concentric embodiment is shaped in standard shapes such as a hockey stick or Judkins Left or Right, liquid pathways used to transfer heat would clearly pinch onto one another, shrinking the internal pathways. Considering the small radius of curvature required for standard guiding catheter shapes, Judkins Left or Right, embodiments using internal liquid flow would likely kink. Because liquid pressure drop is inversely dependent on the hydraulic diameter raised to fourth power or higher, depending on the flow regime (laminar or turbulent), small reductions in liquid pathway size make a substantial increases in fluid pumping pressure requirements. For non-circular pathways the hydraulic diameter is defined as four times the cross-sectional area divided by the wetted perimeter (the perimeter where liquid is touching solid surface).
Regarding heat transfer performance, the liquid flow double concentric embodiment of the device shown in the '383 Ginsburg patent as the preferred embodiment, has several disadvantages. First, the double concentric design limits fluid pumping rates because the hydraulic diameters are inherently reduced due to the concentric nature of the design. The hydraulic diameter in an annulus is the diameter difference between the two enclosing tubes. At small hydraulic diameters high pressures are needed to push liquid to accomplish heat transfer. Pressures that have been used to safely operate cooling devices are in the range of seven atmospheres. At this maximum pressure range the flow will be determined by the fluid viscosity, the path length of the fluid, and the hydraulic diameter. While pressure drop is linearly dependent upon viscosity and path length, it is inversely dependent to the fourth power or higher on the hydraulic diameter. In this case, two design features of the double concentric embodiment as shown in the '383 Ginsburg patent design significantly impede liquid flow: a) the reduced hydraulic diameters; and b) the path length which is double the overall length of catheter. Impeding liquid flow reduces heat transfer coefficients and creates a longer residence time for the liquid to travel the path length. Increased residence times lead to larger liquid temperature changes; the heat transfer liquid in the annulus essentially warms or cools to the surrounding temperatures more readily. Once the liquid temperature change is sufficiently large, the temperature difference between the heat exchange fluid temperature in the annulus and the injected fluid temperature in the inner lumen is eliminated and the device no longer acts as heat exchanger.
Second, the described liquid pathways are parallel flow, in other words the injected liquid is flowing parallel in the same direction as the nearest heat exchange fluid. This arrangement, based on established heat transfer references, inherently limits the maximum possible heat transfer possible substantially, typically 20% to 60% less than counter current flow arrangements depending upon the setup of the heat exchanger. In this case, based on thermodynamics laws, the exiting warm liquid can never have a temperature below the temperature of the cool liquid. In addition, the double concentric design of the device of the '383 Ginsburg patent inherently limits the overall heat exchange process because the returning flow in the outer annulus is exchanging heat with inner annulus flow. In the case of cooling the injected the fluid, the outer annulus flow acts to warm the inner annulus flow since the inner annulus flow has removed heat from the warmer injected liquid flow.
Third, blood flow entry into the inner most or central lumen via the depicted valves of the '383 Ginsburg references is inherently limited. If the flaps as described earlier could be hinged internally, deflected in the described manner, and did not impede placement or removal of interventional tools that include but are not limited to guide wires, dilation catheters, and thrombectomy devices, creating actual blood flow requires a sufficient hydrostatic pressure difference between the external blood flow outside the catheter at the holes and the external blood flow outside the catheter at the distal tip. In the embodiments described in the Ginsburg references, this pressure difference will depend on five factors: 1) the side holes or orifice diameter; 2) the orifice roughness; 3) the stiffness of the flaps; 4) the opening created at the flap; and 5) the pressure drop along the path length along the central lumen. These factors hinder the ability of blood to flow at a fixed pressure difference, an undesirable condition for arterial blood flow to already ischemicly damaged organs.
Fourth, the arrangement and orientation of the valves in the Ginsburg devices, along the shaft perimeter of the patent prevent or at least substantially hinder coolant flow along the length of the catheter. While the patent claims a section distal to the valves is a “temperature altering region”, a means to accomplish this unclear.
In summary, the previously described patents have one or more of these disadvantages:
The designs do not take into account the physical characteristics of existing guide catheters that are based on thirty years of refinement: support for dilation catheter advancement, shape to allow coaxial placement inside arteries for organs at risk, mechanical structure to avoid kinks and ensure placement control, and distal tips that are atraumatic.
The designs are focused on large diameter vessel blood cooling or whole-body cooling, not small artery or organ-specific cooling where flow resistance can easily be increased leading to additional ischemic injury
The designs do not apply heat exchanger best practices well established for decades such as maximizing hydraulic diameters to reduce coolant pressure drop and using counter current flow configurations that maximize the potential heat transfer.
Accordingly, it would be advantageous to develop interventional catheters which accommodate the physical characteristics of existing guide catheters, including support for dilation catheter advancement, which are shaped to allow coaxial placement inside arteries for organs at risk, which have mechanical structure capable of avoiding kinks and ensuring placement control, and which have distal tips that are atraumatic.
It would be further advantageous to develop interventional catheters which are capable of small artery or organ-specific cooling without increasing ischemic injury due to flow resistances.